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A Sparse Regulatory Network of Copy-Number Driven Gene Expression Reveals Putative Breast Cancer Oncogenes
July-Aug. 2012 (vol. 9 no. 4)
pp. 947-954
C. Caldas, Li Ka Shing Centre, Cambridge Res. Inst., Cambridge, UK
C. Curtis, Dept. of Preventive Med., Univ. of Southern California, Los Angeles, CA, USA
Yinyin Yuan, Li Ka Shing Centre, Cambridge Res. Inst., Cambridge, UK
F. Markowetz, Li Ka Shing Centre, Cambridge Res. Inst., Cambridge, UK
Copy number aberrations are recognized to be important in cancer as they may localize to regions harboring oncogenes or tumor suppressors. Such genomic alterations mediate phenotypic changes through their impact on expression. Both cis- and transacting alterations are important since they may help to elucidate putative cancer genes. However, amidst numerous passenger genes, trans-effects are less well studied due to the computational difficulty in detecting weak and sparse signals in the data, and yet may influence multiple genes on a global scale. We propose an integrative approach to learn a sparse interaction network of DNA copy-number regions with their downstream transcriptional targets in breast cancer. With respect to goodness of fit on both simulated and real data, the performance of sparse network inference is no worse than other state-of-the-art models but with the advantage of simultaneous feature selection and efficiency. The DNA-RNA interaction network helps to distinguish copy-number driven expression alterations from those that are copy-number independent. Further, our approach yields a quantitative copy-number dependency score, which distinguishes cis-versus trans-effects. When applied to a breast cancer data set, numerous expression profiles were impacted by cis-acting copy-number alterations, including several known oncogenes such as GRB7, ERBB2, and LSM1. Several trans-acting alterations were also identified, impacting genes such as ADAM2 and BAGE, which warrant further investigation. Availability: An R package named lol is available from www.markowetzlab.org/software/lol.html.

[1] J.R. Pollack, C.M. Perou, A.A. Alizadeh, M.B. Eisen, A. Pergamenschikov, C.F. Williams, S.S. Jeffrey, D. Botstein, and P.O. Brown, "Genome-Wide Analysis of Dna Copy-Number Changes Using Cdna Microarrays," Nature Genetics, vol. 23, no. 1, pp. 41-46, Sept. 1999.
[2] S. Myllykangas, S. Junnila, A. Kokkola, R. Autio, I. Scheinin, T. Kiviluoto, M.-L.L. Karjalainen-Lindsberg, J. Hollmén, S. Knuutila, P. Puolakkainen, and O. Monni, "Integrated Gene Copy Number and Expression Microarray Analysis of Gastric Cancer Highlights Potential Target Genes," Int'l J. Cancer, vol. 123, pp. 817-825, May 2008.
[3] H.M. Horlings, C. Lai, D.S.A. Nuyten, H. Halfwerk, P. Kristel, E. van Beers, S.A. Joosse, C. Klijn, P.M. Nederlof, M.J.T. Reinders, L.F.A. Wessels, and M.J. van de Vijver, "Integration of Dna Copy Number Alterations and Prognostic Gene Expression Signatures in Breast Cancer Patients," Clinical Cancer Research, vol. 16, no. 2, pp. 651-663, Jan. 2010.
[4] P. Platzer, M.B. Upender, K. Wilson, J. Willis, J. Lutterbaugh, A. Nosrati, J.K. Willson, D. Mack, T. Ried, and S. Markowitz, "Silence of Chromosomal Amplifications in Colon Cancer," Cancer Research, vol. 62, no. 4, pp. 1134-1138, Feb. 2002.
[5] K.J. Bussey, K. Chin, S. Lababidi, M. Reimers, W.C. Reinhold, W.L. Kuo, F. Gwadry, Ajay, H. Kouros-Mehr, J. Fridlyand, A. Jain, C. Collins, S. Nishizuka, G. Tonon, A. Roschke, K. Gehlhaus, I. Kirsch, D.A. Scudiero, J.W. Gray, and J.N. Weinstein, "Integrating Data on Dna Copy Number with Gene Expression Levels and Drug Sensitivities in the nci-60 Cell Line Panel," Molecular Cancer Therapeutics, vol. 5, no. 4, pp. 853-867, Apr. 2006.
[6] H. Lee, S.W. Kong, and P.J. Park, "Integrative Analysis Reveals the Direct and Indirect Interactions between Dna Copy Number Aberrations and Gene Expression Changes," Bioinformatics, vol. 24, no. 7, pp. 889-896, Apr. 2008.
[7] R. Menezes, M. Boetzer, M. Sieswerda, G.J. Ommen, and J. Boer, "Integrated Analysis of DNA Copy Number and Gene Expression Microarray Data Using Gene Sets," BMC Bioinformatics, vol. 10, no. 1, pp. 203-217, June 2009.
[8] K. Chin, S. Devries, J. Fridlyand, P.T. Spellman, R. Roydasgupta, W.-L. Kuo, A. Lapuk, R.M. Neve, Z. Qian, and T. Ryder, "Genomic and Transcriptional Aberrations Linked to Breast Cancer Pathophysiologies," Cancer Cell, vol. 10, no. 6, pp. 529-541, Dec. 2006.
[9] R. Tibshirani, "Regression Shrinkage and Selection via the Lasso," J. Royal Statistical Soc., vol. 58, no. 1, pp. 267-288, 1994.
[10] B. Efron, T. Hastie, I. Johnstone, and R. Tibshirani, "Least Angle Regression," Annals of Statistics, vol. 32, no. 2, pp. 407-499, 2004.
[11] R. Brent, Algorithms for Minimization without Derivatives. Prentice-Hall, 1973.
[12] J.J. Goeman, "L1 Penalized Estimation in the Cox Proportional Hazards Model," Biometrical J., vol. 52, pp. 70-84, 2009.
[13] M.A. van de Wiel and W.N. van Wieringen, "Cghregions: Dimension Reduction for Array cgh Data with Minimal Information Loss," Cancer Informatics, vol. 3, pp. 55-63, 2007.
[14] J. Schäfer and K. Strimmer, "An Empirical Bayes Approach to Inferring Large-Scale Gene Association Networks," Bioinformatics, vol. 21, no. 6, pp. 754-64, 2005.
[15] V. Pihur, S. Datta, and S. Datta, "Reconstruction of Genetic Association Networks from Microarray Data: A Partial Least Squares Approach," Bioinformatics, vol. 24, pp. 561-568, Jan. 2008.
[16] L. Breiman, "Random Forests," Proc. Machine Learning, pp. 5-32, 2001.
[17] N. Cristianini and J. Shawe-Taylor, An Introduction to Support Vector Machines : And Other Kernel-Based Learning Methods, first ed. Cambridge Univ. Press, Mar. 2000.
[18] L. Breiman, J. Friedman, C.J. Stone, and R.A. Olshen, Classification and Regression Trees. Chapman & Hall/CRC, Jan. 1984.
[19] K.L. Streicher, Z.Q. Yang, S. Draghici, and S.P. Ethier, "Transforming Function of the lsm1 Oncogene in Human Breast Cancers with the 8p11-12 Amplicon," Oncogene, vol. 26, no. 14, pp. 2104-14, Mar. 2007.
[20] P.M. Watson, S.W. Miller, M. Fraig, D.J. Cole, D.K. Watson, and A.M. Boylan, "Casm (lsm-1) Overexpression in Lung Cancer and Mesothelioma Is Required for Transformed Phenotypes," Am. J. Respiratory Cell and Molecular Biology, vol. 38, no. 6, pp. 671-678, June 2008.
[21] C. Grunau, M.-E. Brun, I. Rivals, J. Selves, W. Hindermann, M. Favre-Mercuret, G. Granier, and A. De Sario, "Bage Hypomethylation, a New Epigenetic Biomarker for Colon Cancer Detection," Cancer Epidemiology Biomarkers Prevention, vol. 17, no. 6, pp. 1374-1379, June 2008.
[22] S. Zhang, X. Zhou, H. Yu, and Y. Yu, "Expression of Tumor-Specific Antigen Mage, Gage and Bage in Ovarian Cancer Tissues and Cell Lines," BMC Cancer, vol. 10, article 163, 2010.
[23] J. Hicks, A. Krasnitz, B. Lakshmi, N.E. Navin, M. Riggs, E. Leibu, D. Esposito, J. Alexander, J. Troge, V. Grubor, S. Yoon, M. Wigler, K. Ye, A.-L. Børresen-Dale, B. Naume, E. Schlicting, L. Norton, T. Hägerström, L. Skoog, G. Auer, S. Månér, P. Lundin, and A. Zetterberg, "Novel Patterns of Genome Rearrangement and Their Association with Survival in Breast Cancer," Genome Research, vol. 16, no. 12, pp. 1465-79, Dec. 2006.
[24] R.W. Wong, "Interaction between Rae1 and Cohesin Subunit smc1 Is Required for Proper Spindle Formation," Cell Cycle, vol. 9, no. 1, pp. 198-200, Jan. 2010.
[25] J. Cuende, S. Moreno, J.P. Bolaños, and A. Almeida, "Retinoic Acid Downregulates Rae1 Leading to apc(cdh1) Activation and Neuroblastoma Sh-Sy5y Differentiation," Oncogene, vol. 27, no. 23, pp. 3339-44, May 2008.
[26] H. Lin, J.-L. Juang, and P.S. Wang, "Involvement of cdk5/p25 in Digoxin-Triggered Prostate Cancer Cell Apoptosis," J. Biological Chemistry, vol. 279, no. 28, pp. 29302-29307, July 2004.
[27] S. Goodyear and M.C. Sharma, "Roscovitine Regulates Invasive Breast Cancer Cell (mda-mb231) Proliferation and Survival through Cell Cycle Regulatory Protein Cdk5," Experimental and Molecular Pathology, vol. 82, no. 1, pp. 25-32, Feb. 2007.
[28] W. Noble, V. Olm, K. Takata, E. Casey, O. Mary, J. Meyerson, K. Gaynor, J. LaFrancois, L. Wang, T. Kondo, P. Davies, M. Burns, Veeranna, R. Nixon, D. Dickson, Y. Matsuoka, M. Ahlijanian, L.-F. Lau, and K. Duff, "Cdk5 Is a Key Factor in Tau Aggregation and Tangle Formation in vivo," Neuron, vol. 38, no. 4, pp. 555-565, May 2003.
[29] P. Labhart, S. Karmakar, E.M. Salicru, B.S. Egan, V. Alexiadis, B.W. O'Malley, and C.L. Smith, "Identification of Target Genes in Breast Cancer Cells Directly Regulated by the src-3/aib1 Coactivator," Proc. Nat'l Academy of Sciences USA, vol. 102, no. 5, pp. 1339-44, Feb. 2005.
[30] D.W. Hein, M.A. Doll, A.J. Fretland, M.A. Leff, S.J. Webb, G.H. Xiao, U.S. Devanaboyina, N.A. Nangju, and Y. Feng, "Molecular Genetics and Epidemiology of the Nat1 and Nat2 Acetylation Polymorphisms," Cancer Epidemiology Biomarkers Prevention, vol. 9, no. 1, pp. 29-42, Jan. 2000.
[31] Y. Benjamini and Y. Hochberg, "Controlling the False Discovery Rate: A Practical and Powerful Approach to Multiple Testing," J. Royal Statistical Soc., vol. 57, no. 1, pp. 289-300, 1995.
[32] B. Burwinkel, M. Wirtenberger, R. Klaes, R.K. Schmutzler, E. Grzybowska, A. Försti, B. Frank, J.L. Bermejo, P. Bugert, B. Wappenschmidt, D. Butkiewicz, J. Pamula, W. Pekala, H. Zientek, D. Mielzynska, E. Siwinska, C.R. Bartram, and K. Hemminki, "Association of NCOA3 Polymorphisms with Breast Cancer Risk," Clinical Cancer Research, vol. 11, no. 6, pp. 2169-2174, 2005.

Index Terms:
tumours,cancer,DNA,genetics,molecular biophysics,RNA,BAGE genes,sparse regulatory network,copy-number driven gene expression,putative breast cancer oncogenes,copy number aberrations,tumor suppressors,cis-acting alterations,trans-acting alterations,passenger genes,DNA copy number,feature selection,DNA-RNA interaction network,GRB7 oncogenes,ERBB2 oncogenes,LSM1 oncogenes,ADAM2 genes,Bioinformatics,Predictive models,Gene expression,Genomics,Breast cancer,Probes,L_1 regression.,Copy-number alteration,gene expression,trans-acting,cis-acting,breast cancer,oncogenes
Citation:
C. Caldas, C. Curtis, Yinyin Yuan, F. Markowetz, "A Sparse Regulatory Network of Copy-Number Driven Gene Expression Reveals Putative Breast Cancer Oncogenes," IEEE/ACM Transactions on Computational Biology and Bioinformatics, vol. 9, no. 4, pp. 947-954, July-Aug. 2012, doi:10.1109/TCBB.2011.105
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